杰克说药丨今年的诺贝尔化学奖咋又给了生物学家？
杰克说药是著名药史专家Jie Jack Li（李杰）教授专为同写意打造的药林外史精品专栏，将讲述一个个药物发现背后的故事。李杰教授现为睿智化学副总裁，先后出版了30本有机和药物化学方面的书籍以及药物发现史，其中10本与诺奖得主E. J. Corey合作完成。其《Blockbuster Drugs》一书获 2015 Alpha Sigma Nu Science Book 奖，并被翻译成中文出版，深受欢迎。
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10月7日，瑞典皇家科学院宣布将2020年诺贝尔化学奖共同授予Emmanuelle Charpentier和Jennifer A. Doudna “开发了一种基因组编辑方法”。她们俩发现了基因技术最锋利的工具之一：CRISPR/Cas9基因剪刀。
在这里，CRISPR是clustered regularly interspaced short palindromic repeats的首字母缩写，而Cas9则是CRISPR-associated gene-9的首字母缩写。这两位科学家从化脓性链球菌 中改造了Cas9酶，从而简化了基因编辑过程。他们具有里程碑意义的论文于2012年6月8日投到美国的 科学 杂志，并于2012年6月20日被接受发表。
就像几乎所有的诺贝尔奖一样，总是有不同的意见。有些人认为立陶宛生物化学家Virginijus Šikšnys可惜了。在Charpentier和Doudna在科学 杂志上发表他们的论文之前，Šikšnys已经证明了cas9蛋白的可编程DNA切割，但他的学校太没名气，他的研究结果很难发表。许多杂志甚至都没有把他的手稿寄出去进行评审就拒绝了他的手稿。
他的文章最终于2012年5月被 美国国家科学院院刊 收到，比Charpentier和Doudna提交的稿件早了一个月，但它却于2012年8月出版，比Charpentier和Doudna的科学论文晚了两个月。你告诉我什么是公平？
许多中国科学家认为，布罗德研究所的张峰被剥夺了诺贝尔奖，因为他和哈佛大学的George Church是第一个在哺乳动物和人细胞上使用CRISPR/Cas9的人。但是张和Church的背靠背科学论文在2013年1月3日的同一期科学 杂志上发表。我知道每个诺贝尔奖有三个名额，但是如果你是在委员会里，张峰还是Church，你会选择谁呢？！更有趣的是， 直到今天，Doudna的伯克利分校和张峰的布罗德研究所之间的专利纠纷仍在法庭上继续。
一个与CRISPR/Cas9相关的小故事是关于贺建奎（有人叫他贺剪刀）。他在2018年的时候，使用了DNA编辑技术删除了CCR-5基因的人类胚胎。并用那些胚胎培育了一对双胞胎女婴，他这不道德的行为严重地违反了全世界科学家广泛接受的基本生命伦理。
就我个人而言，我对今年诺贝尔化学奖的看法是，它又由生物学家获得。毫无疑问，Charpentier 和 Doudna的成就绝对值得一个诺贝尔奖。由于生物化学本身没有诺奖，我认为他们的工作更接近生理学和医学。
更令人不安的是，在过去的十年里，只有两个诺贝尔化学奖给了“真正的”化学。一个是在2010年，Richard F. Heck, Ei-ichi Negishi 和 Akira Suzuki，“在有机合成中钯催化交叉偶联”，另一个是在2016年，给了Jean-Pierre Sauvage, Fraser Stoddart 和 Bernard L. Feringa设计和合成分子机器。
去年，化学诺贝尔奖颁给了锂电池，其中只涉及一些无机化学。2019年诺贝尔化学奖授予发现噬菌体展示肽和抗体。这主要是生物学。2015年用于DNA修复的机理研究，2012年用于GPCR晶体，都是生物。2017年是冷冻电子显微镜的发展，2014年是超分辨荧光显微镜的发展，2011年是准晶体的发现，这三者都是纯物理而非化学。
作为一个化学家，我真诚地希望诺贝尔基金会能够更加关注“纯化学”。这个想法可能太天真，但这只是我个人的意见。
On October 7, the Royal Swedish Academy of Sciences announced that the Nobel Prize in Chemistry 2020 was awarded jointly to Emmanuelle Charpentier and Jennifer A. Doudna “for the development of a method for genome editing.” Charpentier and Doudna have discovered one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. Here CRISPR stands for clustered regularly interspaced short palindromic repeats and Cas9 is acronym of CRISPR-associated gene-9. The two future Nobel laureates reengineered Cas9 from the bacterium Streptococcus pyogenes to simplify the gene-editing process. Their landmark paper were received by Science on June 8, 2012 and was accepted for publication on June 20, 2012.¹
Like almost all Nobel Prizes, there are always dissenting opinions. Some feel that Lithuannian biochemist Virginijus Šikšnys has been cheated out of a Nobel Prize. Before Charpentier and Doudna published their Science paper, Šikšnys already demonstrated the programmable DNA cleavage by the Cas9 protein. But not from a prestigious institution, Šikšnys had a very hard time getting his results published and many journals rejected his manuscript without even sending it out for peer review. His manuscript was eventually received by Proceedings of the National Academy of Sciences (USA) in May 2012, one month before Charpentier and Doudna’s submission, but it was published in August, 2012, two months after Charpentier and Doudna’s Science paper. So you tell me what is fair?
Many Chinese scientists feel that Feng Zhang at Broad Institute has been cheated out of a Nobel Prize because he and George Church at Harvard were the first to use CRISPR/Cas9 on mammalians and human cells. But both Zhang’s and Church’s back-to-back Science papers were published online on the same issue on January 3, 2013. I know that there are three slots for each Nobel Prize. But who would you choose if you sat in the committee, Zhang or Church?! To make things more interesting, a patent dispute between Doudna’s Berkeley and Zhang’s Broad is still on-going in the court.
A side story associated the CRISPR/Cas9 story was Jiankui He back in 2018. In a highly unethical use of the DNA-editing technique, he deleted the CCR-5 gene from human embryos that gave rise to twin baby girls. His exploits violated the fundamental bioethics widely accepted by scientists around the world.
As far as myself is concerned, my contention to this year’s Nobel Prize in Chemistry is that it has gone to biologists. No doubt, Charpentier and Doudna’s achievements definitely deserve a Nobel Prize. Since there is no category in biochemistry per se, their work is closer to Physiology and Medicine if you ask me.
More outrageously, during the last ten years, only two bona fide Nobel Prizes in Chemistry have gone to genuine chemistry. One was in 2010 that went to Richard F. Heck, Ei-ichi Negishi and Akira Suzuki “for palladium-catalyzed cross couplings in organic synthesis” and the other was in 2016 that went to Jean-Pierre Sauvage, Fraser Stoddart and Bernard L. Feringa for the design and synthesis of molecular machines”.
Last year, the chemistry Nobel Prize went to lithium batteries, which involves some inorganic chemistry. The 2019 Chemistry Nobel was awarded to the discovery of phage display of peptides and antibodies. This was mostly biology. The litany goes on and on. 2015 was for mechanistic studies of DNA repair and 2012 was for GPCR crystals, both biology. 2017 was for development of cryo-electron microscope; 2014 was for the development of super-resolved fluorescence microscopy; and 2011 was for the discovery of quasicrystals, all three of which are pure Physics, not chemistry.
I as a chemist, for one, hope that the Nobel Foundation will look more closely to pure chemistry. I am sure the idea is too quaint and naïve these days, but that is just me.
【 1 】Jinek, M.; Chylinski, K.; Fonfara, I.; Hauer, M.; Doudna, J. A.; Charpentier, E. A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity In Science 2012, 337(6096), 816–821.
【 2 】Gasiunas, G.; Barrangou, R.; Horvath, P.; Siksnys, V. Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria In Proc. Natl. Acad. Sci. USA 2012, 109, E2579–2586.
【 3 】Cong, L.; Ran, F. A.; Cox, D.; Lin, S.; Barretto, R.; Habib, N.; Hsu, P. D.; Wu, X.; Jiang, W.; Marraffini, L. A.; Zhang, F. Multiplex Genome Engineering Using CRISPR/Cas Systems In Science 2013, 339(6121), 819–823.
【 4 】Mali, P.; Yang, L.; Esvelt, K. M.; Aach, J.; Guell, M.; DiCarlo, J. E.; Norville, J. E.; Church, G. M. RNA-guided human genome engineering via Cas9 In Science 2013, 339(6121), 823–826.
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